The long-term goal of this project is to determine how the function of mammalian myelinated nerve is disturbed in demyelinating disease. In order to understand better the nature of the dysfunction in the pathophysiological state this has first required an understanding of the normal physiology of the myelinated axon and of the cell that myelinates it, namely (in the PNS) the Schwann cell. Indeed, much of the work in prior grant periods has been devoted to acquiring this understanding. For example, it is now clear that when nerves are demyelinated, they cease to conduct impulses because, as shown both by saxitoxin-binding experiments and by electrophysiological experiments, the exposed internodal axolemma is poor in, or devoid of, Na channels. However, such demyelinated nerves eventually (after a week or so) do acquire the ability to conduct impulses. The question thus raised (still remaining unanswered) is whether the Na channels that must then be present in the now exposed previously myelinated internodal membrane are newly synthesized Na channels carried there by axoplasmic transport from the cell body, or whether they are the channels from the original node that have been redistributed. Or, more intriguingly, does neither explanation apply, but rather the Na channels are being supplied by the ensheathing satellite cells. It is also becoming clear that, contrary to a classical view, the internodal axolemma is not simply an electrophysiologically passive membrane. Rather it displays a diversity of K channels (at least three) that are critical for the maintenance of the resting potential and, as a result, are critical for the repolarisation phase of the action potential in the normal myelinated axon; their role in demyelinated nerve remains to be explored. The fact that these same K channels are present in Schwann cells raises the possibility that, as hypothesized for Na channels, they too may be furnished in part to the nodal axolemma by the satellite cell. Patch-clamp experiments will therefore be done to characterize the electrophysiology and pharmacology of the Schwann cell voltage-gated Na and K channels for comparison with the corresponding axonal channels; and the density of these channels in Schwann cell plasmalemma and axolemma will be determined with 3H-saxitoxin and 125I-a-dendrotoxin, which are specific markers for the respective channels. The specific purpose of the experiments is to gain insight into the function of the satellite cell channels, particularly to explore their role in conduction in normal myelinated nerve and in demyelinated nerve.